| The inflammatory response to be out of control is considered as the major factor in the pathogenesis of infectious diseases and multiple organ dysfunction syndrome (MODS). It is well known that the activation of monocytes/macrophages plays a critical role in inducing the inflammatory response. Macrophages stimulated by LPS or other inflammatory factors produce and release large quantity of various proinflammatory cytokines including TNF-a, IL-1(3, IL-6 and so on. Overproduction of the cytokines can result in systemic inflammatory response syndrome (SIRS) and MODS, which might lead to death. The lung is highly sensitive to LPS to be dysfunctional, suggesting that pulmonary macrophages activated by LPS release some mediators to produce the tissue injury. Pulmonary macrophages consist of three major subpopulations including alveolar macrophages (AMs) located primarily in the alveolar spaces, pulmonary interstitial macrophages (PIMs) which reside within the lung parenchyma, and pulmonary intravascular macrophages. Recently, it was reported that there was a significant increase in production of reactive oxygen intermediates from PIMs, but not from AMs in the rats treated with LPS. The treatment also markedly enhanced phagocytosis only in PIMs and caused a significant increase in chemotaxis of PIMs towards C5a. These data demonstrate that PIMs play an important role in the inflammatory response of the lungs in acute endotoxemia. Therefore, interfering in the overproduction of inflammatory mediators from PIMs may be beneficial in modulating the inflammatory response of the lungs.Previous studies showed that several neuropeptides/hormonesincluding growth hormone, somatostatin, vasoactive intestinal peptide (VIP), cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), neuropeptide Y and neurotensin had anti-shock and anti-inflammation effects, which participated in the central nervous system (CNS)- endocrine system- immune system network regulation. Our laboratory has been studying the effect of cholecystokinin octapeptide (CCK-8) against endotoxin shock (ES) and inflammation. Pretreating ES rats with CCK-8 led to a rise in mean arterial pressure and a reduction in pulmonary arterial hypertension (PAH), and the inflammatory lesions in the lung, liver and spleen tissues were reduced significantly. The mortality rate in ES rat was also lowered by CCK-8. The alleviation effect of CCK-8 on PAH was believed to relate to its inhibitory role in LPS-induced pulmonary inflammatory response. However the mechanism of alleviating the inflammatory response by CCK-8 is not clear. Recently, our laboratory reported that pulmonary macrophages expressed CCK receptor gene, and the expression could be upregulated by LPS, indicating that CCK-8 might bind to CCK receptors and interfere with the overactivation of macrophages induced by LPS.The signal transduction mechanisms through which LPS activates macrophages are anfractuous. However it is undoubtful that the LPS-CD 14-TLR4-IRAK-IKK-1KB-NF-KB-proinflammatory cytokines pathway plays a pivotal role in the macrophage activation induced by LPS. LPS binds to its receptor CD 14 on the membrane of macrophages and activates TLR4 to form LPS-receptor complex. Upon activation, TLR4 most likely form homodimers itself, resulting in the recruitment of an adapter named MyD88. The death domain of MyD88 then recruits downstream IL-1 receptor - associated kinase (IRAK) to the receptor complex. IRAK is then autophosphorylated and dissociated from the receptor complex, and recruits TNF receptor - associated factor 6 (TRAF6) that in turn activates downstream kinases. Several such kinases have been found to be involved in TLR/NF-KB signaling pathways including NF-icB- inducing kinase (NIK) and mitogen-activated protein kinase/ERK kinase kinase 1 (MEKK1). Activated MEKK1 or NIK are individually capable of activating the IKK complex. Subsequently, IicB is phosphorylated and degraded, leading NF-xJB to translocate to the nucleus, and initiating the related gene transcription.
|
PDF Full Text Request